The β ₂ agonist terbutaline specifically decreases pulmonary arterial pressure under normoxia and hypoxia via a adrenoceptor antagonism

Abstract

Pulmonary hypertension is a severe, incurable disease with a poor prognosis. Although treatment regimens have improved during the last 2 decades, current pharmacologic strategies are limited and focus on the modulation of only a few pathways related to endothelin, NO, and prostacyclin signaling. Therefore, the identification of novel molecular targets is urgently needed. We found that the β adrenoceptor (AR) agonists terbutaline (TER) and salbutamol induced a dose-dependent vasorelaxation in large pulmonary arteries but not aortas of mouse. This effect was found to be independent of β ARs and the endothelium but was determined by the type of the preconstrictor. Vasodilation by β AR agonists occurred after pretreatment of pulmonary arteries with phenylephrine and serotonin, both agonists of α ARs, but was absent after preconstriction with the thromboxane analog U46619. These data indicated α-adrenolytic activity of β AR agonists, which was confirmed by a right shift of the phenylephrine dose-response curve by TER. This effect was physiologically relevant because TER also relaxed small intrapulmonary arteries in lung slices and diminished pulmonary arterial pressure in an isolated perfused lung model under normoxia and hypoxia. Finally, TER applied as an aerosol also selectively decreased pulmonary arterial pressure without effects on systemic blood pressure and heart rate in mouse in vivo. Thus, β AR agonists display α-adrenolytic activity in pulmonary arteries ex vivo and in vivo, and may provide a novel option to reduce pulmonary arterial pressure in pulmonary hypertension.-Neumann, V., Knies, R., Seidinger, A., Simon, A., Lorenz, K., Matthey, M., Breuer, J., Wenzel, D. The β agonist terbutaline specifically decreases pulmonary arterial pressure under normoxia and hypoxia via α adrenoceptor antagonism.

The endocannabinoid anandamide is an airway relaxant in health and disease

“…Precision cut lung slices were generated as described previously 33,34 . In detail, mice were sacrificed, the trachea was cannulated and the lungs were filled with a warm solution of 4% low-melting point agarose (6351.5, Carl Roth, Germany) by use of a Saf-T-Intima catheter (Becton Dickinson GmbH, Germany).…”